JP3721180B2 - Access valve device, use of the access valve device in a separation device, and corresponding method - Google Patents

Abstract

An access valve suitable for controlling fluid flow into and out of a chromatography column has a central axially movable probe with a head (71) acting as a spool valve in a barrel (6). Axial movement of the probe adjusts the valve between a fully open condition, in which both a first conduit (73) extending through the probe and a second conduit (51) defined around the probe are open to the column interior, a partly open condition in which a second sealing land (76) on the probe closes the second conduit (51), and a fully closed position in which both conduits are closed. The three positions are useful for packing and unpacking chromatography media into and from the column. In the closed condition of the valve, the first and second conduits (73, 51) communicate with one another so that the valve interior can be cleaned while the column is operating.

Description

  The present invention provides a method and apparatus for controlling fluid flow, for example in chromatography, i.e. mobile phase components by passing the mobile phase through a stationary phase or residual phase in order to cause separation of the mobile phase components. The present invention relates to a method and an apparatus for causing separation of substances and separating substances.

  Chromatography is generally a well-established and valuable technique in both preparatory and analytical work as well as purification. A typical industrial chromatographic apparatus has an upright housing in which a normally packed bed of particulate material rests on a permeable retaining layer. The fluid mobile phase enters, for example, through an inlet at the top of the column, usually through a porous, perforated, mesh, or other permeation restricted layer, through a packed bed, It is typically taken from an outlet below the layer with limited transmittance.

  Changing the packing material bed to make it old or to carry out another process is a daunting task, especially in large industrial columns, which can be up to several hundred liters in capacity. . Usually existing floors are dense and difficult to remove. The housing must be removed and the compacted mass should be crushed and removed. Furthermore, if the column is to be effective, the new bed must be packed very evenly. That is, fresh material must be carefully added while maintaining liquid flow. The device usually must be kept clean, especially for bio-products, the system requires high sterility for weeks or months. A single small pollution can be very damaging.

  Conventionally, it took a lot of time to replace the used packing in the large column.

  UK application GB-A-2258415 describes a column that can be filled and unloaded without disassembling the column using special supply and discharge valves on the top and bottom plates of the housing. The packing supply valve has a spray nozzle that can be retracted into the top plate, and the spray opening is closed or advanced by a seal on the top plate and protrudes into the column bed space and is pumped into a slurry of packing material (slurry ) For opening. The discharge valve has an advanceable nozzle with a radially directed spray opening at its widened head, which is located coaxially within a wider hole in the bottom plate. When retracted, the head fits into the hole and seals the head itself and the hole. To empty the column, the nozzle is advanced and the buffer is pumped into the nozzle. The nozzle head advances to disperse the medium being filled, and the pumped buffer carries the medium through the larger holes that are currently open.

  These valve assemblies have difficulty maintaining long-term hygiene.

(Summary of Invention)
Therefore, another invention is proposed.

In one embodiment, a separation apparatus is provided having a column housing with a housing wall that defines an enclosed floor space that includes a bed of packing material in use. The housing wall includes end walls at both ends of the floor space (as viewed from the direction of the working fluid flow) and has an inlet opening and an outlet opening for fluid communication with the floor space in use. An access valve device communicates with the floor space through the housing wall at the access location. The valve device has first and second adjacent fluid flow conduits, each conduit having an external connection and an internal opening near the interior of the housing wall. From the outside of the housing wall, the valve device
A first closed state in which both the first conduit and the second conduit are isolated from the floor space;
A second partially open condition wherein the apparatus connects the first conduit to the floor space but isolates the second conduit from the floor space;
A controllable adjustment can be made between a third open condition in which the device communicates both the first conduit and the second conduit to the floor space.

  This type of access valve offers many possible operational advantages. Some of them will be described later. One feature it can provide is the filling and removal of floor space through a single housing wall facility.

  For removal, the valve is moved to a third open state in which both the first conduit and the second conduit are open towards the floor space. The fluid is forced through the first conduit to pulverize and disperse the packed bed, after which a flowable dispersion of the packing material flows out through the second conduit.

  Preferred features for these purposes include:

  The opening in the first conduit can have a fixed or adjustable spray nozzle or other throttle hole that helps to break up the bed by flow rate. Providing multiple outlet openings also helps to reach a larger floor space area and remove it more effectively.

  The access valve device preferably comprises a probe that can be advanced from the retracted state retracted into the housing wall into the floor space to crush the material therein. The crushing probe is preferably a movable valve element that defines one or both of the conduits, the first conduit at the valve outlet (on the head of the probe as described in UK application GB-A-2258415, or on the head It is preferable that it can be installed through.

  The opening in the second conduit can also form an outlet from the floor space. This is preferably a single hole. It preferably has a cross-sectional area that is at least substantially proportional to the cross-sectional flow area within the second conduit itself. It is generally desirable that the cross-sectional area of the second conduit passing through the valve device is greater than the cross-sectional area of the first conduit.

  To fill, the access valve device can be adjusted to a second partially open condition, forcing the filling material through the first conduit, typically as a particle dispersion in the carrier fluid. The carrier fluid escapes from the floor space through an outlet away from the valve device, while the filler material is retained during that time.

  Thus, by maintaining the flow of carrier fluid through the accumulation bed and exiting through the permeable end retainer, the permeable end is spaced from the position of the valve device, preferably at the position of the housing wall opposite the position. The retainer can be filled with a new bed of filler material. This flow of carrier fluid may involve the injection of floor material through the first conduit.

  The valve device preferably has a relatively movable valve component or valve element that can be in face-to-face contact with each other or moveable, and defines a first conduit and a second conduit. Such a pair of elements may be sufficient to define a first conduit and a second conduit, as well as sufficient sealing portions or lands to block the internal opening for the three states described above. . Each spaced apart sealing part in one part or element is a single state or a plurality of differently spaced sealing parts in another intermovable part or element, the first state and the second state. Can be engaged in a sealed state.

  The relative movement between the valve elements across the three states can be straight (generally in the direction through the housing wall, preferably perpendicular), rotation (generally around the direction axis as described above), Or a combination thereof, that is, a linear movement with the action of a screw. These three states preferably correspond to three spaced positions along a predetermined single rotation, straight line or combination (eg, spiral) path or track for such relative movement.

  For ease of explanation, such a valve element isolates the first conduit from the floor space in the closed state and isolates the second conduit from the floor space in the partially open state. I will have. This land may be on said valve element fixed to the housing wall provided at or near the mouth of the valve device. The opening of the first conduit and the second conduit can then be defined by another valve element or elements that can be slidably moved relative to this sealing land.

  Valves such as those suggested above are useful not only for controlling the housing of the separation device, but also for managing the flow into and out of all vessels or conduits.

  For the components of the separation device that the components of the separation device are washable in situ (CIP), i.e. not removed from the device, and most preferably not disturbing the floor space, for example during the course of the separation, It is also a particularly desirable characteristic for other situations.

  In another embodiment, the separation device is in an access valve that manages communication between the first conduit and the second conduit through the housing wall of the separation device floor space as described above, or through the wall of the container or conduit to the space. Suggests that this can be achieved by placing the valve in a closed state, in which both the first conduit and the second conduit are isolated from the space, and a continuous cleaning path along the first conduit, for example It is defined through the cleaning recess in the valve device connecting between the first conduit and the second conduit and along the second conduit. The valve device component is shaped so that all areas of the cleaning path are flushed, i.e. there is no dead space, for at least one direction of cleaning fluid flow along the cleaning path. In particular, for at least one said flow direction, at any point of the valve device, the surface of the first conduit, the second conduit, or the connecting recess is at a right angle or more than the central flow axis (or of the flow path). It is preferred that, depending on the shape, it does not diverge from the layer) or converge towards the central flow axis and diverge or converge at an angle of 70 degrees or more.

  One particular proposal provides the possibility of a flow path in a three-state valve device as described above having a relatively movable valve element, one of the valve elements being the other in the first state. Isolation that seals against the first opposing sealing surface of the element and, in the second state, against the second opposing sealing surface of the other element, isolates the first and second conduits from the floor space, respectively. Has a seal. According to Applicants' proposal, one valve element defines a recess behind its isolation seal, which provides a gap around the second sealing surface of the other element when closed. The first fluid conduit and the second fluid conduit are in communication with each other.

  In the separation device, the preferred location of the access valve in any of the embodiments described above is in the housing end wall structure. This end wall is generally permeable to fluids, but the associated filler material does not permeate through, for example, a porous, perforated or mesh layer, ie a filtration layer. The access valve opening is open on the floor space side of this layer. In order to introduce a fluid material, usually a sample phase or a mobile phase, behind said filtration layer, for example along a third conduit extending through the end wall alongside the valve device, generally a further opening is provided. It has been.

  Another embodiment provides for the use of an access valve device as described above to remove material from the column bed space, and in an additional version this may form part of the separation method.

  This additional version allows the liquid containing the components to be separated to move upward through the bed of granular stationary phase (packing medium) confined in the column housing bed space, for example at a rate that expands or fluidizes the bed. It is related with the separation process made to flow. After passing through the bed, the liquid passes through a permeation limiting element (typically a mesh or other porous or other perforated layer holding the packing medium particles) and exits the column housing via the process outlet. .

  The liquid may be contaminated with particulate or agglomerated substances that do not pass through or freely pass through elements with limited permeability. Biological cultures are an important example of this. For example, extended bed separation is used to remove targeted proteins by adsorption onto bed particles from uncleaned or partially cleaned fluid culture media containing cells, cell debris, lipid particles, and the like.

  As the separation proceeds, such materials accumulate on the permeation limiting element used to prevent escape of the packing material through the process outlet. Over time, accumulated material can interfere with effective operation. The process must then be stopped, the column housing opened, the accumulated material removed and restarted.

The applicant's proposal is
In the permeability limiting element, by opening a cleaning outlet for accumulated material at or near the permeability limiting element and in direct communication with the floor space, so that the accumulated material exits through the cleaning outlet. By forcing the cleaning flow of fluid to disturb the accumulated material,
Such accumulated material may be removed from the bed space, for example, as the process proceeds, sometimes and optionally without stopping the feed liquid flow.

  Thus, the separation process can be continued with reduced or eliminated interruptions to remove accumulated material from the bed space.

  The clean flow is forced by forcing the reverse flow through the permeability limiting element, e.g. back through the process outlet, or through other conduits through the impervious wall after the permeability limiting element. It can also be supplied. Additionally or alternatively, by pumping fluid out of one or more nozzles on the floor space side of the element, for example in the middle of the element and preferably with a cleaning flow radiating from a conduit passing through the housing wall A clean stream can also be emitted from these nozzles.

  These functions are provided by the access valve device as disclosed in the above embodiments.

  Another proposal related to such a process is to move the moving bed through a direct input opening, which is preferably controlled by a valve, rather than through a permeability limiting element provided to hold the inlet side of the packed bed. Related to introduction into the column bed space. For example, the introduction may be through an access valve device opening that passes through the transmittance limiting element.

  In this way, a mobile phase containing particulate material or other material that may block the permeability limiting element can be conveniently introduced into the bed for processing. The access valve device used for the introduction may be any of those described above, for example.

  This proposal can be combined with previous proposals to expedite the introduced particulate or other material from the floor space.

  Another embodiment provided herein is a valve device for managing the flow entering the space through the housing wall or conduit wall, for example for a chromatography column housing wall. The valve device has an external barrel element that defines an axial direction. The barrel has an internal bore extending axially from the outer end to the inner end of the barrel with axial openings at both ends. The opening at the inner end constitutes a valve port and provides a radially inward port that seals the surface of the hole.

  An elongated spool element extends axially through the barrel hole and is movable axially relative to the barrel hole. The central fluid conduit extends axially through the spool element and is open near the barrel mouth, preferably as a spray nozzle, preferably by a plurality of radially oriented openings. The spool element has a first radially outwardly directed inner seal land disposed on an inner surface axially of the central conduit opening and with respect to the barrel mouth seal surface at a first relative longitudinal position of the spool element relative to the barrel. And is adapted to seal, thereby isolating the central conduit opening from the valve mouth.

  The spool element also has a second radially outwardly facing seal land disposed on the outer surface in the axial direction of the central conduit opening and facing the barrel mouth seal surface at a second relative longitudinal position of the spool element relative to the barrel. Adapted to seal against, wherein the central conduit opening is exposed to the interior space. Outside the second seal land, there is preferably an annular gap between the spool element and the barrel hole. This gap constitutes an axially extending external fluid conduit that is isolated from the valve port by a second land seal at a second intermediate position.

  At the third internal position of the spool element relative to the barrel, the second seal land is away from the mouth seal surface and both the internal and external conduits are open to the interior.

  This valve device is suitable for use in all of the above embodiments.

  The barrel hole may also have a recess disposed outside the mouth seal surface to connect the inner conduit opening to the outer conduit in the fully closed position.

  The valve can be installed in a wall with a valve opening inside and outside the wall, and a connecting manifold is connected to the outer conduit at the outer end of the barrel and the inner conduit of the spool element. With movable communication coupling to. Means are also provided for driving a controllable movement of the spool element. This can take a variety of forms that one skilled in the art can prepare without difficulty. For example, as disclosed in UK application GB-A-2258415, a spool element is screwed onto a manifold or other fixed component and a drive means is actuated to rotate it to a controlled range, as desired. You may make it give this axial movement.

  In the separation device, the valve may be installed in an end wall having an inner transmittance limiting layer and an outer impermeable wall layer so that the valve port communicates with the transmittance limiting layer. The outside of the valve mouth barrel can also overlie the permeation limiting layer. In order to introduce process fluid into the floor space, one or more process conduits are formed as one or more gaps between the valve barrel and the impervious layer around the end wall, for example alongside the valve barrel. It extends to the rear of the transmittance limiting layer through the impermeable wall layer.

Embodiments proposed by the applicant will now be described in detail with reference to the accompanying drawings.
(Detailed description of the invention)
FIG. 1 schematically shows the general components of a chromatography column 1. The column has a cylindrical fluid-impermeable side wall 11 made of a high strength / reinforced polymer material, which may be, for example, stainless steel or translucent. The open upper and lower ends of the side wall 11 are closed by the upper end assembly 12 and the lower end assembly 13. Each end assembly has a fluid impervious end plate 3 that fits hermetically to close the opening in the cylindrical wall 11, which end plate 3 is made of a high strength engineering plastic material such as stainless steel or polypropylene. It is preferable that The end plate is lined by a metal holding plate 2, which presses the outer surface of the end plate and protrudes radially at the end of the side wall as a holding flange 22 and is adjusted through the holding flange 22. A possible tension rod 14 is secured. These tension rods 14 connect the upper end assembly 12 and the lower end assembly 13 and help the structure withstand high fluid pressures.

  Each end plate 3 has a central through-opening 31 for communicating between the exterior of the column and the packed bed space 9 defined by the side wall 11 and the end assemblies 12, 13. Access through opening 31 is subdivided into individual conduits connected externally through connection manifold 8.

  A filtration layer 4, typically made of filterable or woven plastic or steel, extends over the floor space 9 on the inner surface of the end plate 3. The inner surface 35 of the end plate 3 is recessed in a conical shape, for example, as shown in the figure behind the filtration layer 4, and using a support rib (not shown) that supports the filtration layer 4 from the rear, It is preferable to define the filtration space 34 during this time. The moving bed conduit 33, which is one of the connecting conduits, is open toward the inside of the filtration space 34 on the inside and toward the moving bed connector 81 of the manifold 8 on the outside.

  From the manifold 8, the access valve device 5 protrudes inwardly through the end plate opening 31 and further through the central opening 41 of the filtration layer 4 in a sealing manner. The access valve 5 manages the bypassing of the filter layer 4, i.e., directly connecting one or more conduits from the manifold 8 to the floor space 9, as will be described in more detail below. Here, the first and second valve-type conduits 51 and 61 managed by the valve 5 and connected to the outside through the connector 82 of the manifold 8 are shown.

  In a typical operation of the column, the packed bed of granular fixed bed material fills the bed space 9 between the upper filtration layer and the lower filtration layer 4. Since the valve device 5 is closed, the mobile phase is supplied through the mobile phase connector 81 (arrow A), enters the filtration space 34 through the conduit 33, then passes through the filtration layer 4 and is discharged through the packed bed, Separation of components. The eluate passes through the filtration layer 4 of the lower end assembly 13 and flows out through the mobile phase connector 81 of the lower end assembly (arrow B) and is collected as appropriate.

  FIG. 1 and the above description show the overall relationship of the components and the typical mode of operation. Those skilled in the art will know and will be apparent from the following description that other specific structures and modes of operation may be suitable for various processes.

  Here, a more detailed embodiment of the end plate and the valve structure will be described with reference to FIGS.

  The manifold 8 is provided as a machined metal or plastic block that is hermetically secured over the central opening 31 of the end plate 3 by means of a threaded connector 88 and is provided by means of bolts 21 or other suitable stops. Retracted into the central hole 23 of the external metal holding plate 2 fixed to the end plate 3. The outer edge of the end plate 3 is sealed against the column side wall 11 by an annular polymer sealing member 32 that also overlaps the filtration layer 4 and supports the outer edge. The seal member may have an internal rigid reinforcement. Unlike conventional O-rings, this seal member is sealed by a cylindrical surface and the end plate shape is fitted into the recessed groove to eliminate dead space.

  The manifold 8 has a central hole 91 which is coaxial with the central opening 31 and has a threaded connection opening 83 facing inward and a threaded connection opening 89 facing outward. The cylindrical barrel 6 of the spool valve 5 is screwed into the inward connection opening 83, extends coaxially inward through the central opening 31, passes through the central circular orifice 41 of the filtration layer 4, and passes through the filtration layer. 4 ends in an outward flange 65 that overlaps 4. A cylindrical outer sleeve 66 fits snugly around the barrel 6, its outward edge stops against the inner surface of the manifold block through a polymer seal ring 662, and its inner edge passes through another polymer seal ring 661 to filter layer 4. It stops against the outer surface and confines the layer 4 between the sleeve 66 and the barrel flange 65. Since the outer diameter of the barrel corresponds to the outer diameter of the layer orifice 41, removing the barrel without removing the barrel and removing it inside will not remove the barrel without obstructing the filtration layer 4 in the illustrated state. Is possible. This is advantageous for column maintenance.

  One or more flow conduits 33 are created by the gap between the barrel assembly (barrel and sleeve) and the end plate opening 31. Thus, the end plate opening 31 can have a plurality of axially extending channels distributed around it to form a conduit 33, the intervening surface of the opening 31 being compatible with the barrel assembly. Alternatively, a complete annular gap can be provided. Alternatively, these conduits may be provided away from the barrel assembly and only defined through the material of the end plate 3. The inner end of the conduit 33 communicates with the filtration space 34. The outer end of the conduit 33 is sealingly aligned (by polymer seal rings 662, 663) with a manifold block connecting conduit 811 commonly connected to a threaded or other connectable port 81. This establishes direct fluid communication between the filtration space 34 and the port 81, while at the same time passing through the filtration layer 4 inevitably allows communication between the floor space 9 and the port 81. Ribs provided (in a well-known manner) on the inner plate surface 35 help to evenly distribute or collect fluid into or from the space 34.

  A hole 61 extends axially from one end to the other through the barrel 6. The outer end of the hole is sealed into the central manifold hole 91 (by the polymer seal ring 664) and the diameter has not changed. The inner end of the hole 61 is on the floor space side of the filtration layer 4 and constitutes the opening 611. The hole 61 has a uniform cylindrical cross section, except for a radially expanded portion near the outside of the opening 611. The extended portion 612 has a central cylindrical portion bounded on either side by a tapered surface 613. These make an angle within 45 degrees from the axis.

  The central probe element 7 operates in the hole 61 and provides the function of a spool valve. The probe element 7 has a long tube 72 with an open internal hole 73 that extends from near the barrel opening 611 through the outer end of the barrel 6 and the coaxial ball 91 of the manifold 8. Outside the end of the outer barrel, a tapered seal ring 665 seals between the tube 72 and the surrounding manifold ball 91 and a plug collar 87 is screwed into the manifold's external connection 89 to taper the seal 665. Hold in place.

  At its inner end, the probe 7 has a sturdy head 71 with a pointed tip 74 and terminates the hole 73. The head 71 has a cylindrical sealing surface 711 of the same diameter as the barrel hole 61, which is shown in the drawing at the opening 611 of the barrel hole 61 assisted by an embedded polymer seal ring 641 as shown. The sealing surface 64 can be sealed.

  The probe holes 73 are open at a set of spray openings 75 (FIG. 4), which open through the tubes 72 and are distributed around the tubes 72. The tip seal surface 711 is swollen in the radial direction from these openings 75. Directly outside the opening, the probe head 71 has another radial extension or land 76 having a cylindrical sealing surface 761 bounded by a tapered portion 762 that is angled less than 45 degrees from the axis.

  Outside this second extension 76, the tube exterior 72 is a simple cylinder.

  The diameter of the sealing surface 761 on the second expansion portion 76 is the same as the diameter of the sealing surface 711 on the first expansion portion 71.

  Since the tube 72 is narrower than the barrel ball 61, an annular cross-sectional gap 51 is defined between them. This constitutes an external valve conduit that extends through the outer end of the barrel 6 and into the manifold hole 91 to the seal 665, which diverts to a threaded or otherwise connectable manifold port 82.

  At the tip of the manifold 8, the outer end of the probe tube 72 is coupled to means for advancing or retracting the tube 72 by sliding it through the seal 665. This means is a motor activated, as described for example in GB-A-2258415, for example, to advance the probe 7 by rotating a fixed drive member which engages the tube 72 via a screw, for example. Alternatively, it may be a servo. In addition or as an alternative, manual control for axis adjustment is provided.

  The spool valve effect of the valve 5 is as follows.

  FIGS. 2 and 3 show the first closed state, in which the head seal land 711 seals the open sealing surface 64 of the barrel and isolates both valve conduits 51, 73 from the floor space 9. The filtration conduit 33 is not affected by the valve. The nozzle opening 75 and the second seal land 76 are aligned with the radially expanded portion 612 of the barrel hole 61 in the axial direction. This causes the nozzle opening 75 to communicate with the external valve conduit 51 and create a continuous, sealed flow path between the probe tube hole 73 and the manifold port 82. There are no unswept areas or dead spaces in this flow path. Inside the valve device 5, there is no departure from the local central flow axis / layer at 45 degrees or more at this interface, which aids in effective sweeping. Within the manifold, there is no dead space in the path as well.

  Thus, when the chromatography column is in operation (see also FIG. 7), the valve device and its associated connections are passed through the fully sweepable wash path (eg, an aqueous alkaline solution or the art). It is possible to perform appropriate cleaning by supplying other appropriate cleaning medium known in the above. In particular, it is conceivable to feed the cleaning solution into the probe tube 72.

  FIG. 4 shows a state in which the second part of the valve 5 is opened. The probe tube 72 is advanced sufficiently to align the second seal land 76 with the opening 611, and their respective seal surfaces 761, 64 provide a sliding seal. This also moves the nozzle opening 75 to the outside of the opening 611 and communicates with the floor space 9. Thus, the inner valve conduit consisting of the holes 73 is in direct communication with the floor space and bypasses the filtration layer 4 while the outer valve conduit 51 remains isolated from the floor space 9.

  FIG. 6 shows one application example of a valve when making a new packed material bed. The filling itself can be as described in UK application GB-A-2258415. Specifically, a flowable slurry of filler material particles in the carrier liquid is pumped through the tube 72 and sprayed radially from the openings 75 in the direction dispersed around. As the packing material accumulates in the bed space 9, excess carrier fluid escapes through the filtration layer 4 and exits through the manifold port 81 where the filtration conduit 33 and connecting tube are secured. This is continued until sufficient filler material has been introduced.

  FIG. 5 shows the third state of the valve. In this case, the probe tube 72 is further advanced inwardly to move the second seal land 76 away from the opening seal 64, where the opening seal 64 is opposed to the smaller diameter outer surface of the tube 72 to create an external valve. The conduit 51 is opened to the floor space 9 through the opening 611.

  FIG. 8 shows how to take advantage of this third state to remove material from the column bed. As disclosed in UK application GB-A-2258415, the advanced pointed head 71 of the probe 7 is suitable for crushing existing floor material which is often in a tight dense mass. It should be noted that this helps the removal of the material. A carrier liquid, such as a buffer, is pumped through the probe hole 73 and out through the nozzle opening 75, and its fast nozzle speed assists in the crushing and floating transport of the filled material. Particulate packing material cannot pass through the filtration layer 4 but is exhausted along the connected tube so that it passes through the valve port 611 and along the external valve conduit 51 as a slurry port manifold port 82. It is possible to respond to the inflow by the liquid pump.

  For the first time, a single column wall device allows both column packing and packing removal. This can provide tremendous flexibility in column operation. Note that the packing and unloading operations can be accomplished entirely from the outside of the column housing without the need to disassemble or remove the end assembly. Furthermore, the valve itself that can do this can be properly washed while the column is in operation by introducing a mobile phase onto the bed through a filtration conduit 33 as shown in FIG. Thus, even this relatively precise wall system does not pose a risk of accumulation of contaminants and leaching into long-term operation processes that would be accompanied by serious damage. In terms of those skilled in the art, the valve device is a “hygienic” device.

  Furthermore, since the probe 7 can be completely removed from the barrel hole 61, the valve is easily disassembled for maintenance.

  Another mode of use for the expanded bed separation process is described with reference to FIGS. Extended bed adsorption is a recently developed separation technique, particularly to reduce or eliminate the need to clean the biological culture before eluting the biological culture through the packing to separate the desired components. is there. The packed bed is expanded by an upward flow of liquid medium so that uniform particulate material in the sample can travel through the bed to an outlet above the bed. In order to expand, the bed must remain on the permeable layer, through which an upward flow of liquid is established. Thus, sample introduction should generally occur as a single stream, and then sample batches elute through the bed. Usually, the desired substance is adsorbed onto the bed particles, and in the next step, the liquid is stopped by stopping the upward flow of the liquid, and the floor is compressed by lowering the top plate, and then the liquid that desorbs the target substance from the bed particles. It is recovered by filtering through the bed.

  The column for this can have an upper holding assembly and a lower holding assembly, each having an impervious plate inner filtration layer and a central valve device, as shown in the previous figure. Regular filtration conduits and means for establishing a mobile phase upflow are also provided.

  The first feature in this case is the expansion of a sample, such as an uncleaned fluid culture medium, bypassing the lower filtration mesh by injecting the sample through the inner valve conduit 73 of the lower valve with the second part open. It can be conveniently introduced into the floor. If the sample is injected intermittently, the lower valve is returned to the first state where the valve is fully closed between each injection. Thus, the new valve structure of the present invention provides a convenient way to introduce such samples beyond the mesh required to maintain upflow.

  A second highly significant feature is described with respect to FIG. 9, which shows in more detail the top and bottom assemblies for the expanded floor process.

  During normal operation of the process, the mobile phase passes through the filtration layer 4 'and exits through the filtration conduit 33'. Granular debris and other materials, such as lipids, that obstruct the passage of the filtration layer 4 'gradually accumulate. This therefore accumulates in the upper floor space area 91 near the filtration layer 4 '. Over time, maintaining proper flow is hindered.

  By moving the upper valve device 5 'to the third fully open state for a short time, this material is removed from the external valve conduit by creating a cleaning liquid stream near the filtration layer 4' to disturb the accumulated material. 51 can be discharged out of the floor space along with the cleaning liquid stream. One way to achieve a cleaning flow is to supply a short jet of a suitable liquid, such as a buffer, through the probe hole 73 'and out through a nozzle opening 75' near the filtration layer 4 '. Alternatively or additionally, the normal flow direction of the buffer out of the system (arrow X) is temporarily reversed and the buffer is pumped back through the filtration conduit 33 '(arrow Y), thereby passing through the filtration layer 4'. A temporary downward flow is created (arrow Z) and the material is crushed so that the accumulated material can exit the valve conduit 51 with the escape of the temporary liquid pressure wave. This can be done with or without stopping the sample feed at the bottom of the column.

  Thus, as long as the adsorption proceeds efficiently, the process can be run without having to stop for other reasons. This is a very advantageous technique.

  FIG. 10 shows a modified end plate structure for a chromatography column. Differences from the previous embodiments are as follows.

  The filtration layer 4 is formed integrally with the inner ring 41 and the outer ring 42 in one member of a plastic material. The inner ring 41 forms a coplanar end for the barrel 6 of the central bulb 5 and has an inwardly facing surface that forms a seal with the central probe of the bulb. This coplanar one-piece construction further reduces the risk of contamination at the access point. This also allows the inner periphery of the filtration layer to be confined within the groove of the valve barrel 6 so that the barrel 6 can be a single component instead of two components. The end cell and valve component may be polypropylene.

  The outer ring 42 of the filtration layer is used to hold the filtration layer in place by confinement between the column wall 11 and the end plate 3 of the cell, which in this variant is a one-piece polypropylene product. .

  The connecting manifold 8 has a mobile phase inlet / outlet port 81 and a waste slurry outlet port 82 that is inclined outward rather than vertical as in the previous embodiment to improve flow. Another significant feature in this embodiment is that the filtration layer 4 is concaved by the support ribs on the end plate 3 formed with slanted edges rather than slightly radially oriented. That is. It can be seen that this slight conical shape improves drainage from the column being washed.

  FIG. 11 schematically illustrates another embodiment of a valve that implements a similar concept. Here, the central moving probe is not a fluid delivery nozzle but a simple armature. The enlarged head 171 is carried on the actuating rod 272 and has a flat end surface 1712, a first outer seal land 1711, a conical converging portion 1613 towards a narrow recess or waist 1612, and a second seal surface. It has a smaller enlargement 176 with 1761.

  As in the previous example, the mobile phase conduit 33 is provided outside the valve barrel 6. Inside the valve barrel, a central fluid conduit 173 is defined by an internal conduit wall 172 surrounding the probe shaft 272 rather than by the probes 272, 171, which has an opening with an inwardly directed seal 174. However, this opening is recessed from the main opening through the filtration layer 4 and this main opening is inside itself at the mouth of the outer conduit defined between the outer barrel wall 6 and the inner conduit wall 172. Has a facing seal 141.

  FIG. 11 shows the central probe fully advanced to open both conduits, for example, to remove the column packing, and the fully open valve. The filling removal liquid is pumped into the internal conduit 173 and ejected from around the armature head 171. That is, the waste slurry flows in and out through the external conduit.

  For example, in the partially open position for filling the column, the armature is partially retracted so that the second sealing surface 1761 removes the seal of the inner conduit and the outer conduit remains open. The slurry can be pumped into the external conduit. This shears the slurry below the spray nozzle of the first embodiment.

  When the armature is fully retracted, its front surface 1712 is flush with the filtration layer 4 and its first head seal surface 1711 is hermetically joined with the central filter open seal 141 to close the outer conduit. At the same time, the second seal land 176 falls below the inner conduit seal 174, and the inner conduit seal 174 then faces the recess 1612 to allow proper circulating cleaning flow through the inner and outer conduits.

  Note that in the open state, the conical portion 1613 of the head 171 can be changed axially to change the direction of liquid pumping. This embodiment shows how two separate seals on the fixed part of the valve can have the same effect as before when their spacing is different from the spacing of the corresponding sealing part of the movable part. Is shown.

It is the schematic sectional side view which shows the basic characteristics of a chromatography column. It is an axial sectional view showing the end plate structure in more detail. It is an expanded axial direction sectional view which shows the structure of an access valve. FIG. 3 is an axial sectional view according to FIG. 2 with the access valve in a partially open position. FIG. 3 is an axial section according to FIG. 2 with the access valve in the fully open position. It is an axial sectional view of an end plate showing a medium filling operation. FIG. 7 is a diagram according to FIG. 6 with the column operating and the access valve being cleaned. FIG. 7 is an axial cross-sectional view according to FIG. 6 showing a step of taking out the packing medium from the column. It is an axial sectional view of an upper end plate of a chromatography column subjected to extended bed chromatography showing a washing operation. FIG. 9 is an axial cross-sectional view of a deformation of the column end of FIGS. It is the schematic of the 2nd modification of an access valve.

Claims (12)

A separation method for separating a target component from a liquid incorporating the target component together with other components,
A medium is adapted to hold a target component, the bed of the medium is confined within a bed space defined by a column housing, and the housing holds a process outlet and a particulate packed medium in the bed space Providing the bed of granular packing medium having a permeability limiting element between the process outlet and the floor space;
In order to expand the bed in the bed space and achieve separation of the target component from a fluid by holding on the granular packing medium, the granular packing via the permeability limiting element and the process outlet Flowing a fluid upward through a bed of media;
Fluid flows upwardly through the bed of the granular packing medium, through the permeability limiting element, and through the process outlet to expand the bed into the bed space, over the granular packing medium Achieving separation of the target component from the fluid by holding
The other component of the fluid includes particulate matter, and the particulate matter accumulates against the permeability limiting element during the flow of the fluid; and
Opening a washing outlet in direct communication with the floor space at or near the permeability limiting element;
Forcing a fluid wash flow against the permeability limiting element, disturbing the particulate matter that has accumulated on the permeability limiting element, and allowing the substance out of the floor space via the cleaning outlet A separation method comprising a passing step.   The separation method according to claim 1, wherein the fluid includes an unpurified or partially purified cell liquid medium, and the target component is a protein product in the liquid medium.   The separation method according to claim 1, wherein the washing flow includes a reverse flow forced in a reverse direction through the transmittance limiting element.   The separation method according to claim 1 or 2, wherein the washing flow is forced through at least one nozzle on the floor space side of the permeability limiting element.   The separation method according to claim 4, wherein the nozzle is on a conduit in the middle of the transmittance limiting element, and the wash stream extends radially from the nozzle. The column housing has a housing wall and an access valve is provided through the housing wall and a permeability limiting element to allow direct communication of the first and second fluid flow conduits to the floor space; An access valve is adjustable between a closed state in which the two conduits are isolated from the floor space and an open state in which the two conduits are open to the floor space;
The access valve is adjusted during the method to the open position where the second fluid flow conduit provides the cleaning outlet and the cleaning flow of fluid is introduced via the first fluid flow conduit. Item 2. The separation method according to Item 1.   The column housing has an inlet-side permeability limiting element, and the flow includes pumping a liquid medium through the inlet-side permeability limiting element to expand the bed; An inlet-side access valve movable between is provided for direct communication with the floor space, and the liquid containing the target component is passed through the inlet access valve into the floor space through the open state. The separation method according to any one of claims 1 to 6, which is directly introduced.   The separation method according to claim 7, wherein the inlet-side access valve is opened at a center of the inlet-side permeability limiting element. A separation method for separating a target component from a liquid incorporating the target component together with other components,
The medium is adapted to hold a target component and the medium bed is confined in a bed space defined by a column housing, the housing separating the bed space from the method inlet, the method inlet The granule, having a permeability limiting element, a process outlet, and an outlet-side permeability limiting element separating the floor space from the process outlet, wherein both transmittance limiting elements hold a granular packing medium in the floor space Providing the bed of filling medium;
Via the method inlet and upwardly via the inlet side permeability limiting element, the inlet side permeability limiting via the bed of granular packing medium to expand the floor in the floor space. Introducing a liquid flow through the element and through the process outlet;
A separation method comprising the step of directly introducing a mobile phase material containing a target component into the floor space through an input opening provided with a valve.   The separation method according to claim 9, wherein the input opening is via an access valve device extending through the inlet-side permeability limiting element.   The separation method according to claim 9 or 10, wherein the mobile phase material incorporates a particulate substance.   The separation method according to claim 11, wherein the mobile phase material includes an unpurified or partially purified cell liquid medium, and the target component is a protein product in the liquid medium.

Images